Prevymis

A therapy for CMV (cytomegalovirus) prophylaxis

Indication:
PREVYMIS is indicated for prophylaxis of cytomegalovirus (CMV) reactivation and disease in adult CMV-seropositive recipients [R+] of an allogenic haematopoietic stem cell transplant (HSCT).¹

PREVYMIS is the first CMV DNA terminase inhibitor, providing patients with a path of protection from the start of their hematopoietic stem cell transplant.¹

With its mechanism of action, PREVMYIS targets a component of the terminase complex involved in viral DNA cleavage and packaging, which restricts drug activity to the virus alone. Cross-resistance is therefore not likely with agents with a different mechanism of action.

Mode of Action – video

Dosing

PREVYMIS offers once daily dosing¹

PREVYMIS can be initiated before or after engraftment- and you may start as early as the day of the transplant

• Start PREVYMIS prophylaxis as early as day 0 and no later than day 28 post-transplant.
• Continue PREVYMIS prophylaxis through 100 days post-transplant
  • PREVYMIS prophylaxis beyond 100 days post transplant may be of benefit in some patients at high risk for late CMV reactivation.
    • The safety of PREVYMIS has for >100 days not been studied in clinical trials.
• Use of PREVYMIS for >100 days has not been studied in clinical trials and requires careful assessment of benefit-risk balance.

Efficacy

Demonstrated Efficacy in CMV Prophylaxis¹

PREVYMIS demonstrated efficacy over placebo in the primary end point: clinically significant CMV infection at week 24 (NC=F approach)^a,b

Efficacy across R+ HSCT Patient Subgroups¹

Proportion of R+ patients with clinically significant CMV infection at week 24 (NC=F approach)

Safety profile

Demonstrated safety profile of PREVYMIS for CMV prophylaxis in aduld R+ HSCT patients¹

Summary of uncommon adverse reactions identified in clinical trials for PREVYMIS

Frequencies are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) or very rare (< 1/10,000).

HSCT and CMV background

Overview of CMV Progression in Allorgenic HSCT Recipients

CMV reactivation in allogeneic HSCT recipients can occur early and lead to complications, including:^2-4

• CMV end-organ disease.²
• Morbidity and mortality.^2,4
  • Any level of CMV viral load is associated with an increased risk of overall mortality.⁴

CMV end-organ disease includes²

Overview of CMV Progression in Allogeneic HSCT Recipients

• Primary CMV infection is the first detection of CMV infection in an individual who has not previously been exposed to CMV.^2,5
• After primary infection, CMV may remain latent. Immunocompromised individuals, such as allogeneic HSCT recipients post-transplant, are at risk for reactivation, also known as recurrent CMV infection, and subsequent progression to CMV disease and other associated complications.^2,6
• CMV infection is considered to have progressed to reactivation when viral loads have become detectable in the blood. CMV viral loads can be determined through a variety of methods, including antigenemia, RNAemia, or DNAemia.^2,7
• In allogeneic HSCT recipients, CMV infection and disease can lead to various complications and are important causes of morbidity and mortality.^2,4
• CMV disease occurs when clinical signs and/or symptoms are present and when there is detection of CMV in the tissue of the relevant organ in the transplant recipient.^2,4
• CMV end-organ disease can include CMV pneumonia, CMV GI disease, CMV encephalitis, CMV hepatitis, and CMV retinitis.²
• CMV reactivation and any level of CMV viremia are associated with an increased risk of mortality in the first year post-transplant in allogeneic HSCT recipients.⁴
• CMV reactivation has been shown to occur early post-transplant, with >30% of HSCT recipients who were CMV seropositive or had a seropositive donor found to have CMV infection within 1 month post-transplant.⁴
• Another study evaluating the incidence of CMV reactivation through day 100 post-transplant found CMV reactivation to occur as early as day 0 post-transplant.³

GI=gastrointestinal.

All CMV-Seropositive Recipients are at high risk for CMV reactivation

• Positive CMV serostatus (R+) prior to allogeneic HSCT is an important risk factor for CMV primary infection and reactivation.^8,9
• CMV infection has been shown to occur in approximately 30%-65% of CMV-seropositive allogeneic HSCT patients.^6,10

Proportion of CMV infection in CMV-seropositive allogeneic HSCT patients^6,10

All CMV-Seropositive Recipients Are at High Risk for CMV Reactivation^8,9

• For allogeneic HSCT recipients, CMV seropositivity (R+) is an important predictor of CMV primary infection and reactivation.^8,9
• CMV infection has been shown to occur in approximately 30% to 65% of CMV-seropositive allogeneic HSCT patients without CMV prophylaxis.^6,10
• These findings were supported by two retrospective studies. The first was a retrospective multivariate analysis of data from the CIBMTR database of patients who received their first allogeneic HSCT between 2003-2010 (n=9,469), and the second was a retrospective cohort study of 305 allogeneic HSCT recipients from January 2008 through December 2012.^6,10

CMV Can occur early post-transplant¹

More than 30% of HSCT recipients who were CMV seropositive or had a seropositive donor had CMV infection within 1 month post-transplant.⁴

CMV Reactivation Has Been Shown to Occur Early Post-Transplant^3,4

A study evaluating the incidence of CMV reactivation through day 100 post-transplant found CMV reactivation to occur as early as day 0 post-transplant.⁴

Another retrospective study found that >30% of allogeneic HSCT recipients who were CMV seropositive or had a seropositive donor experienced CMV viremia within 1 month post-transplant.³

CMV reactivation occurred in 643 (69%) recipients by day 100 post-transplant based on any level of viremia.³

Study Design

Hammerstrom et al was a retrospective cohort study conducted in 115 consecutive adult recipients who underwent a haploidentical allogeneic HSCT from March 2009 through April 2014 and evaluated the incidence of CMV reactivation through day 100 post-transplant.2 Green et al was a retrospective noninterventional cohort study evaluating 926 allogeneic HSCT recipients between January 1, 2007, and February 28, 2013.³

Allogeneic HSCT recipients who were CMV seropositive or had a seropositive donor were observed for 1 year post-transplant for CMV disease or death, with weekly CMV testing by PCR until day 100 post-transplant.³

For most patients PET was initiated based on a viral load threshold of 125 IU/mL.³

IU=international units; PCR=polymerase chain reaction; PET=preemptive therapy.

References

1. Prevymis SPC, 06/2023
2. Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials. Clin Infect Dis. 2017;64(1):87–91.
3. Hammerstrom AE, Lombardi LR, Pingali SR, et al. Prevention of cytomegalovirus reactivation in haploidentical stem cell transplantation. Biol Blood Marrow Transplant. 2018;24(2):353–358.
4. Green ML, Leisenring W, Xie H, et al. Cytomegalovirus viral load and mortality after haemopoietic stem cell transplantation in the era of pre-emptive therapy: a retrospective cohort study. Lancet Haematol. 2016;3(3):e119–e127.
5. Crumpacker CS II. Cytomegalovirus (CMV). In: Bennet JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, PA: Elsevier Inc; §2015:1738–1753.
6. Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427–2438.
7. Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin N Am. 2011;25:151–169.
8. George B, Pati N, Gilroy N, et al. Pre-transplant cytomegalovirus (CMV) serostatus remains the most important determinant of CMV reactivation after allogeneic hematopoietic stem cell transplantation in the era of surveillance and preemptive therapy. Transpl Infect Dis. 2010;12(4):322–329.
9. Hakki M, Aitken SL, Danziger-Isakov L, et al. American Society for Transplantation and Cellular Therapy Series: #3-prevention of cytomegalovirus infection and disease after hematopoietic cell transplantation. Transplant Cell Ther. 2021:27:707-719. doi: 10.1016/j.jtct.2021.05.001.
10. Sousa H, Boutolleau D, Ribeiro J, et al. Cytomegalovirus infection in patients who underwent allogeneic hematopoietic stem cell transplantation in Portugal: a five-year retrospective review. Biol Blood Marrow Transplant. 2014;20(12):1958–1967